The present invention relates to diverse combinatorial libraries, processes and apparatus, in particular to diverse libraries of compounds incorporating amide scaffolds.
Discovery of new therapeutic compounds for treating diseases has typically involved screening individual compounds against targets representative of a particular disease of interest. The iterative process relies upon finding a compound having at least a minimal level of activity in an assay and then synthesizing as many derivatives of the lead compound as possible. The derivatives tested would form the basis of a xe2x80x9cstructure-activity relationshipxe2x80x9d (SAR) which would hopefully provide insight for designing a lead compound. Often the process is repeated time and again before any lead is uncovered. The obvious and major drawback in this drug discovery process is the generation of compounds on a one-at-a-time basis requiring much labor, time and expense.
Advances in robotics and solid-phase chemical synthesis has spawned the combinatorial approach for preparing libraries of compounds which makes synthesizing thousands of diverse compounds feasible. What once took months or even years by the traditional approach has become possible in a matter of weeks and even days through combinatorial chemistry, thereby drastically reducing the time, labor and expense involved in drug discovery.
The combinatorial approach has been adapted for preparing vast libraries of oligomeric compounds such as peptides and non-oligomeric small organic molecules on the order of 102 to 106 discreet compounds. Theoretically the total number of compounds in a library is limited only by the number of available reagents for forming substituents on a central scaffold.
The present invention provides amide compounds of formula (I): 
wherein:
each R1, R1xe2x80x2, R4, R5 and R5xe2x80x2 is, independently, H, an amino protecting group, or CH2, CH(R2), Cxe2x95x90O, Cxe2x95x90S, S(xe2x95x90O)2, C(xe2x95x90O)NH, C(xe2x95x90S)NH or C(xe2x95x90O)O substituted with H or a hydrocarbyl group selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C20 alkynyl, C6-C14 aryl, C6-C14 aralkyl, C3-C14 cycloalkyl, C5-C14 fused cycloalkyl, C4-C14 heterocycle, C4-C14 heterocyclylalkyl, C4-C14 heteroaryl, C4-C14 heteroarylalkyl and CH(R2)xe2x80x94NHxe2x80x94R2; wherein said hydrocarbyl group is optionally substituted with oxo, acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy, provided that R1xe2x80x2 may also be a solid support and R4 is not H; and
each R2 and R3 is, independently, H or a hydrocarbyl group selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C20 alkynyl, C6-C14 aryl, C6-C14 aralkyl, C3-C14 cycloalkyl, C5-C14 fused cycloalkyl, C4-C14 heterocyclyl, C4-C14 heterocycloalkyl, C4-C14 heteroaryl and C4-C14 heteroarylalkyl; wherein said hydrocarbyl group is optionally substituted with acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol or thioalkoxy, provided that R2 is not H.
The present invention also provides combinatorial libraries comprising a plurality of amide compounds of formula
In another aspect of the present invention there are provided methods for preparing amide compounds of formula (I) comprising:
attaching an amine to a solid support to form a solid support-bound amine of formula (II) wherein SS is a solid support; 
xe2x80x83reacting compound (II) with an FMOC-protected amino acid to form an amide compound of formula (III); 
xe2x80x83replacing the FMOC protecting group on the amino acid with a sulfonyl protecting group to form an amide compound of formula (IV); 
xe2x80x83reacting the secondary amine moiety of the compound of formula (IV) with a protected aminohydroxy compound of formula (V) wherein Pg is a protecting group; 
to form an amide compound of formula (VI); 
xe2x80x83removing the sulfonyl protecting group of the compound of formula (VI) to form an amide compound of formula (VII) bearing a protected terminal primary amine moiety and a secondary amine moiety; 
xe2x80x83reacting the secondary amine of the compound of formula (VII) with an R4 building block to form an amide compound of formula (VIII) bearing a protected terminal primary amine moiety; 
xe2x80x83removing the protecting group on the terminal primary amine moiety to form an amide compound of formula (IX); and 
xe2x80x83reacting the deprotected primary amine moiety with an R5 building block to form an amide compound of formula (X). 
Also provided, in accordance with the present invention, are methods further comprising cleaving amide compounds of formula (X) from the solid support to form amide compounds of formula (I).
The present invention also provides pharmaceutical compositions of amide compounds of formula (I).